The present invention deals with the combination of several anti-oxidants, including enzymatic co-factors and thiol compounds, and various tissue and cell growth stimulating factors in appropriate delivery vehicles employed in a topical carrier as a means of both minimizing and ameliorating and also concomitantly repairing free radical damage to the skin from ultraviolet radiation and also stimulating the growth, differentiation and maturation of epidermal cells resulting from environmental and metabolic factors.
When cutaneous tissues are exposed to radiation such as solar ultraviolet rays (UVA and UVB radiation), damage to the skin ensues, particularly UVB which results in sunburn and tanning. Chronic UV ray exposure contributes to the skin aging process, the so-called photoaging process and in many cases to the development of cutaneous malignancies. Many common pathological factors exist as the various layers of skin are injured from local release of free radical species, emanating from cellular metabolism and enhanced by environmental UV radiation injury, while the skin is exposed to oxygen in the atmosphere as well as ozone, smog, smoke and other pollutants.
The skin repair processes are common to environmental and dermatologic conditions. Cutaneous tissues so exposed to injury, such as UV radiation with resulting xe2x80x9cburns,xe2x80x9d react so that water molecules contained within cells are altered as are lipids of membranes and of extracellular tissues resulting in the formation of a number of noxious free radicals. This phenomenon on the body has also been called oxidant stress and the free radicals are also known as reactive oxygen species. The latter two are known as the process of lipid peroxidation.
Ultraviolet radiation is responsible for the effects of sunburn and tanning of the skin. Moreover, both short and long wave length ultraviolet light contribute to the skin""s photoaging and the development of the various types of skin cancer. Photoaging enhances the chronologic changes of skin, known as chronoaging. Ultraviolet B radiation exerts its most harmful effects when the sun is high on the horizon (high noon hours). In contrast, ultraviolet A radiation is more variable with time of day and time of the year making protection to UVA radiation a year round requirement. Sun care products should protect against both UVA and UVB radiation.
Ultraviolet radiation consists of short wave length, high energy UVB rays (290 NM to 320 NM) and longer wave length, lower energy UVA radiation (320 NM to 400 NM). The former is responsible for the range of sunburn damage from slight erythema to painful burns and blistering. These are acute phase effects. In contrast, UVA radiation penetrates the skin""s deeper layers, epidermis and dermis, and is more responsible by its attack on collagen for the so-called premature aging of skin or photoaging. Both UVA and UVB by their creation of free radicals may act synergistically on the pathogenesis of skin cancers. In the laboratory, acute phototoxic reactions using the chemical psoralen and ultraviolet A rays have been used to study dermatologic pathologic responses and concomitant repair processes. Skin reactions, such as acute sunburn, includes redness (erythema) and swelling (edema), with resulting infiltration of the dermal layers by inflammatory cells (polymorphonuclear leukocytes, lymphocytes and macrophages) and pigmentation of the overlying skin by stimulation of melanocytes. Besides the aging process, the chronic UV radiation damage may lead to cutaneous malignancies, particularly squamous and basal cell carcinomas, and in many instances to malignant melanomas.
There is a worldwide epidemic of skin cancer. Announcements say xe2x80x9cfry now, pay later.xe2x80x9d In Australia, Sid Seagull, pictured on the beach, urges and reminds all to play it safe in the sun xe2x80x9cSlop! Slip! Slap! Slop on the sunscreen, slip on the shirt and slap on the hat.xe2x80x9d Although there are some variations among countries, the incidence for the three major skin cancers has risen steadily during this century. Most disturbing are the progressive high mortality rates for malignant melanomas. All three neoplasias are associated with ultraviolet radiation exposure, the culture of sun loving and a tanned skin, the diminishing ozone layer, and complicating environmental pollutants. Since World War II, in the USA and other countries, family incomes have risen with more leisure time available for outdoor activities with faster transportation to exotic tropical areas for more sun exposure. This is coupled with modern scant clothing styles for all ages and genders.
In basal cell carcinomas, epidemiologic studies suggest that exposure to the sun up to age 20 initiates a process of carcinogenesis which manifests itself as a neoplasia many years later, particularly as our generations live longer. Exposure to sunlight induces changes in the DNA of epidermal cells and suppresses the local immune system. Moreover, as we age our ability to repair DNA injury emanating from solar damage is markedly reduced. Basal cell carcinomas with an incidence rising from age 30 and a peak at age 70, develop typically in cutaneous exposed areas with strong evidence of chronic sun damage such as wrinkling, irregular pigmentation, collagenosis, telangiectasias and solar keratoses. Early clinical recognition of these lesions is imperative with subsequent complete surgical extirpation.
Squamous cell carcinoma is the second most common skin cancer with a greater morbidity (case fatality rate is 7 per 1000) due to its more aggressive features. This cancer is also on the rise with its true incidence difficult to calculate due to underreporting as lesions are often excised in doctor""s offices. Higher case rates are recorded for Caucasians than for Hispanics, Japanese and African-Americans in various series published in the literature. Cutaneous lesions related to squamous cancers include intraepidermal or invasive keratinocyte dysplasias, including solar keratoses and Bowen""s Disease. For squamous cell carcinoma a major constitutional risk factor is skin type, which is clinically graded by the reaction of unprotected skin to strong sunlight. The risk is highest for those individuals least able to tan; however, the incidence in Australia is 70 per 100,000 even in those who xe2x80x9cjust tan but don""t burn.xe2x80x9d Sunlight is the major environmental carcinogen for these neoplasias, particularly UVB with a wave length range of 290 to 320 NM. Although UVA may also play a role, cumulative UV dose is most important in the etiology of this cancer. Early diagnosis and prompt removal of squamous cell carcinoma is paramount. The Skin Cancer Foundation champions their excellent self examination brochure with xe2x80x9cSkin Cancer: if you can spot it, you can stop it!xe2x80x9d
Although the incidence of malignant melanoma is certainly lower than the two aforementioned carcinomas, the case fatality rate is much higher for melanoma. The mortality rate from the tumor is rising albeit novel therapeutic modalities. Anatomic distribution of melanomas among white populations is predominantly the trunk in males and the lower extremities in females. A strong hypothesis for etiology of melanoma states that intermittent and intense sun exposure of susceptible (untanned) subjects is more important than total lifetime solar exposure. Proximity of residence to the Equator is another risk factor. In addition, association of high sun exposure during childhood with melanoma is related to a higher appearance of numbers of common melanocytic nevi in the exposed skin. This lesion is regarded as both a marker with an elevated risk and a precursor of melanoma. Freckles in adolescents is another strong yet independent risk factor for melanoma. Intense and intermittent sun exposure leads to greater stimulation of the normal function of melanocytes resulting in their proliferation and an increase in cellular melanin production. This occurs because of an increased synthesis of melanocytexe2x80x94stimulating hormone receptors, which occurs concomitantly with attempts at repair of DNA damage caused by sun radiation.
In 1996, the Centers for Disease Control and Prevention in Atlanta and the American Academy of Dermatology have launched a rigorous and ample campaign for melanoma/skin cancer detection and prevention. Others have followed with prominent nationwide alerts and advertisements. Although prevention with avoidance of peak sun hour exposure, protective sunscreens and clothing are beneficial, an added therapeutic preventative is the concomitant use of synergistic antioxidants and sun blockers as in the preparations of the present application to combat and reduce free radicals and their putative cutaneous injury generated by ultraviolet radiation.
Investigators such as Burke et al. as noted in U.S. Pat. No. 4,865,840 conducted experiments in rodents to determine whether oral and/or topical selenomethionine supplementation could reduce the incidence of acute and/or chronic damage to the skin. This included sunburn and pigmentation as well as the development of skin cancers, respectively. These controlled studies showed that the concentration of selenium in skin in areas of topical application of the lotion containing selenomethionine were greater than those of the experimental animals given comparable oral doses. The selenium concentration of untreated skin and liver tissue were similar to those of animals receiving the oral selenium compound. There was no evidence of selenium toxicity in any of the experimental animals. The mice treated with selenomethionine had significantly less skin damage by ultraviolet irradiation, as indicated by reduced inflammation and pigmentation and by later onset and lesser incidence of skin cancers.
Selenium has been shown to be an effective inhibitor of skin tumor promotion in rodent skin, but the mechanism is not precisely known. Perhaps the common inciting factor by the carcinogens is the generation of toxic radicals. Selenium, as the co-factor of the enzyme glutathione peroxidase, detoxifies hydrogen peroxide and hydroperoxides within cells. This selenium-glutathione complex may lower the level of potentially damaging peroxide radicals that are generated from various carcinogenic promoting chemicals and radiation energy.
Histopathologically, acute ultraviolet exposure which causes sunburn (so-called solar erythema) is associated with the development of altered epidermal cells becoming dyskeratotic and known as sunburn cells. Likewise, this UV injury has been shown to alter epidermal Langerhans cells which are essential in the cutaneous immune response, by activating helper T lymphocytes. Although accounting for only 2-4% of the epidermal cell populations, Langerhans cells are photodamaged by acute UV rays which results in impaired immune responses locally. Epidermal cells have also been shown to become depleted of their reduced glutathione content and in these studies dermal edema and increases in epidermal ornithine decarboxylase (an enzyme which correlates with epidermal cell damage) were related to the quantity of UV doses applied. Glutathione depletion in both epidermis and dermis was not related to cell leakage but to its consumption in the cell as an antioxidant. L-glutathione locally imparts a prime protective effect on the skin as the solar rays generate free radicals. Topical sunscreens ameliorate but do not prevent sunburn damage. The present invention is based upon the realization that local cutaneous antioxidants will reduce the damage which is caused by the ensuing free radical species.
During the process of phagocytosis by polymorphonuclear leucocytes (PMN), an increased consumption of oxygen occurs. This xe2x80x9crespiratory burstxe2x80x9d generates superoxide radicals (O2xe2x88x92), hydrogen peroxide (H2O2), the hydroxyl radical (OHxe2x88x92) and hypochlorous acid (HOCl). Hydrogen peroxide is derived from the free oxygen species by a process called dismutation while, in the presence of catalytic iron, the hydroxyl radical peroxidizes polyunsaturated fatty acids in cell membranes, which occur in high concentrations in the skin. The ensuing lipid peroxidation decreases membrane fluidity with loss of cellular receptor function. Also, aldehyde derivatives are produced and released which are capable of inhibiting protein synthesis and blocking macrophages.
In skin, oxygen radicals are also made by fibroblasts. Following ultraviolet or thermal burns, there is an increased level of the enzyme xanthine oxidase in the skin, which also generates free oxygen radicals. These free radicals also have effects on gene activation during inflammatory processes in the skin, for they rapidly induce breaks in DNA. These genes encode transcription factors, which play roles in induction of cellular growth, differentiation and development.
The skin is a highly vascular organ, exposed to high levels of atmospheric oxygen and of ultraviolet rays, UVA, UVB and UVC radiation, the latter particularly in ozone depleted zones. The former is essential for the genesis of oxygen free radicals, while the solar radiation is a most potent inducer through UV stimulation of the noxious cellular reactive oxygen species.
Teleologically, the skin""s surface has a well developed endogenous oxidant defense system to combat free radicals including the enzymes superoxide dismutase, catalase, selenium dependent glutathione peroxidase and the ubiquitous thiol tripeptide, glutathione, in its reduced form. Also present in the epidermis are the nutritionally provided vitamins C and E, including the hydrophilic antioxidant dehydroascorbate and the lipophilic antioxidant alpha tocopherol, respectively. These two vitamins may also be provided for local use in compositions disclosed herein.
Ultraviolet radiation, particularly UVB, causes acute damage to the skin (sunburn) resulting in a cutaneous inflammatory response. Clinical symptoms include discomfort, pain, tenderness, itching, while local signs include erythema and edema. Skin inflammation associated with itching results in scratching, which further traumatizes the sunburned skin. This trauma causes bleeding into the affected tissues, such that hemoglobin is released from the red blood cells. As aforementioned, when the hemoglobin is exposed to the hydrogen peroxide generated from neutrophils and xanthine oxidase in inflamed tissues, there is hemoglobin degradation and consequent release of catalytic iron ions and toxic free heme and a hemeferryl (iron) species which are themselves capable of initiating lipid peroxidation. These events in sunburned skin aggravate the skin""s inflammatory response, the exposed lesions of sunburn skin damage and the consequent excoriations from the pruritus make these sunburns more likely to become infected by secondary bacterial contamination of the wounds.
In addition, cells subjected to oxidative stress may severely affect cellular function and cause damage to membrane lipids, to cytoskeletal structure and to DNA. Free radical damage to DNA has been measured as formation of single-strand breaks, double-strand breaks and chromosomal aberrations. Cells exposed to ionizing radiation and cigarette smoke have also been demonstrated to have an increased intracellular DNA damage. Tissues exposed to radiation result in the breakage of water molecules, with consequent production of the potent hydroxyl radical. This reactive free species sets up a variety of deleterious biochemical chain reactions, including interactions with purine and pyrimidine bases, thereby affecting DNA. Similarly, in clinical conditions which include chronic skin injury due to solar radiation, the aging process, and radiation injury, oxygen free radicals have been shown to be mutagenic and pathogenic of DNA structure and thus DNA changes are related to increased frequency of associated malignancies, including the three types of skin cancer, squamous and basal cell carcinomas and malignant melanoma.
It has been found that sunscreens alone are inadequate in protecting skin from UV radiation and in repairing skin so damaged. There are two types of sunscreens:
1. Reflectants which contain zinc oxide or titanium dioxide;
2. Absorbents, examples of which include P-aminobenzoic acid, benzophenone, methoxycinnamates and salicylates.
Both groups protect against ultraviolet rays A and B radiation depending on the composition of the sunscreen. Evidence shows that sunscreens with high protective factors suppress the development of a premalignant cutaneous lesion called actinic keratoses. Thus, sunscreens may also be useful when used regularly for years in the primary prevention of carcinomas and malignant melanomas. Photo protection is certainly mandatory in those patients who have already experienced one skin tumor in an attempt to prevent a second cutaneous malignancy over sun exposed body surfaces. Although sunscreens protect well against acute sunburn, users should not be lulled into complacency about the amounts of sun exposure they are receiving in order to prevent ultraviolet ray skin damage, creation of free radicals at exposed cutaneous sites, and promotion of dermatologic malignancies. This concern over skin cancers and photoaging has resulted in the use of sunscreen products for daily use including moisturizers and foundation make-up products. These concerns similarly have contributed with the marketing of outdoor UV protectants with high SPF values, many above 15, some above 30 SPF.
The FDA has long ago approved reflectant sunscreen products. Titanium dioxide and zinc oxide are both inorganic chemicals with very little known potential of causing skin irritation or sensitivity to these. However, it becomes more difficult with these inorganics alone to deliver higher SPF values. Moreover, these two must be adequately dispersed within the sunscreen or cosmetic preparations. Other requisites are that the inorganic sunscreens remain dispersed throughout the shelf life of the product and must remain dispersed with the film that is formed on the surface of the body following its application. It has also been shown that sunscreens based solely on inorganics are usually not resistant to wash off following perspiration in the hot outdoors or on contact with water in pools, lakes and seas. Others find that these lack acceptable aesthetic or sensory characteristics. Thus, to achieve higher SPF values, organic active FDA approved sunscreen ingredients are necessary, added to the inorganic formulations or alone as exist in many commercial products. The most common organic ingredient is octyl methoxycinnamate, which has been shown to protect both within the UVB rays and the short UV-A bands. To increase formulations with SPF above 15, it is necessary to use organics with greater absorbency within the UV-A bands of the spectrum. This most commonly used sunscreen is benzophenone-3 (oxybenzone).
In addition to the above, it is hypothesized that when tissues are exposed to radiation, energy is absorbed by water contained within the cells resulting in breakage of the oxygen-hydrogen covalent bonds of the water molecule leaving hydrogen and hydroxyl radicals in situ. It is known that the hydroxyl radical is quite reactive in its interaction with other biomolecules generally thought to be responsible for setting off chain reactions including interactions with the purine and pyrimidine bases of nucleic acids. Many of those who have studied the effects of ultraviolet and gamma radiation on the human body believe that radiation-induced cutaneous carcinogenesis are initiated by free radical damage.
Animals with epithelial tumors have been shown to have increased blood glutathione (GSH) levels. Similarly, higher glutathione levels were detected in groups of humans with disseminated gastric adenocarcinoma and in those with localized or locally advanced skin carcinoma without metastasis. Mean blood GSH levels were 78% and 31% higher, respectively, when compared to control subjects. In blood, most of GSH is present in the red blood cells and may reflect the body""s reaction to produce its prime antioxidant, GSH, in response to epithelial malignancies. The rate of generation of GSH within the red blood cells may indicate the body""s protective response to reactive species, free radicals, released into plasma by tumors and inflammation.
Antioxidants have been found it all stages of carcinogenesis whereas other antioxidants are more specific and thus more effective against tumor initiation or promotion or tumor progression. Glutathione and selenium have been shown to play prime roles in protection of carcinogenesis, the latter particularly in skin tumors, when selenium is applied locally as selenomethione, selenium yeast extract or other thiol bonds but also in preventing other cancers, when selenium is taken orally thereby replenishing selenium body stores. Likewise, glutathione, the most abundant tissue thiol and antioxidant, inhibits carcinogenesis, as stated, and indeed when its concentration is suppressed by chemicals so that glutathione levels are significantly lowered, chemical carcinogenesis is enhanced and progression of tumor numbers and tumor size increases.
The role of intracellular GSH in irradiated cancer cells has been investigated. Reducing the intracellular levels of GSH in tumor cells increases their sensitivity to irradiation or oxidant damage mediated by activated neutrophils or macrophages. Inhibition of GSH synthesis also augments lysis of murine tumor cells by sulfhydryl-reactive anti-neoplastics. Thus, neoplastic cells depleted of their endogenous protective antioxidant, GSH, are more sensitive to radiation damage. Conversely, other studies have shown that increases in intracellular GSH are beneficial. An L-cysteine delivery agent not only enhanced endothelial cell GSH concentration, but also protected these cells in an inverse, linear relationship from damage by endogenous hydrogen peroxide. This preventive role of GSH is of value in treating skin which has been exposed to ultraviolet radiation.
It is thus an object of the present invention to provide a composition useful in minimizing early and acute ultraviolet radiation damage, as well as late and chronic radiation induced photo damage which together may enhance or cause photoaging of the skin.
It is yet a further object of the present invention to provide in the form of a topical carrier, certain antioxidants which are effective in reducing ultraviolet radiation-induced cutaneous carcinogenesis which is initiated and promoted by the formation of cutaneous free radicals.
It is yet a further object of the present invention to provide reparative epidermal growth factors to promote skin repair and wound healing from acute sunburn and chronic ultraviolet radiation induced photoaging processes in the skin.
These and further objects will be more readily apparent when considering the following disclosure and appended claims.
The present invention is directed to a composition and method for reducing the effects of ultraviolet radiation induced skin damage. The composition comprises an effective amount of a glutathione and selenium (as selenoamino acid or selenium yeast extract) as the co-factor of glutathione peroxidase. The combination can be in the form of a lotion, cream, ointment, gel, spray, balm, emulsion and foundation cosmetic preparations and lipsticks and may also include the further endogenous antioxidants acetyl-l-carnitine and superoxide dismutase as well as secondary exogenous components to be discussed hereinafter, plus the epidermal and/or fibroblast growth factors to aid in the tissue repair process by inducing orderly epidermal cell growth and maturation.
As previously noted, the present invention deals with reduced L-glutathione (GSH), in combination with selenium and thiol compounds used topically to act as free radical scavengers reducing ultraviolet radiation-induced skin changes. It is proposed that the described active ingredients be employed in topical compositions. Topical carriers are employed which should be both non-irritating to the skin and which are suitable for delivering the active components to the skin. Further, suitable topical carriers should be those which do not inhibit the antioxidant activity of the active ingredients thus reducing the efficiency of the composition for protecting the skin from the effects of acute and chronic ultraviolet radiation. Further, such carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for chronic topical administration to the skin and be free of bacterial contaminants.
Certain antioxidants, particularly the endogenous L-glutathione, superoxide dismutase and acetyl L carnitine, as well as the element selenium, a co-factor for the enzyme glutathione peroxidase, and thiol compounds such as L-cysteine, can be employed in suitable carriers such as lotions, solutions, creams, ointments, balms, sprays, aerosols, gels or foundation compositions to protect and to treat the overlying skin surface as a result of the putative acute and chronic UV radiation etiologic factors in specifically dealing with the effects of the various free radicals on biomolecules, lipids, and cell membranes. Moreover, specific cellular growth factors, such as epithelial and fibroblast growth factors in appropriate concentrations and delivery vehicles, are incorporated in the preventive and reparative preparations of this invention for aiding the repair of UV radiation damage of skin and healing of the superficial wounds as occurs in sunburns and in the chronic UV radiation injury known as photoaging of the skin.
Without being bound to any particular theory, it is noted that reduced glutathione is employed in protecting cells and aerobic organisms against oxidative stress by itself being oxidized. Thus, L-glutathione must act in combination with other enzyme systems in order to be reduced so that it may renew its role as a free radical scavenger. GSH functions also coordinately with the enzyme glutathione peroxidase to break down hydrogen peroxide and lipid hydroperoxides. Glutathione peroxidase in the body requires selenium as a cofactor to exert its biologic antioxidant function. Selenium compounds have been shown to scavenge oxygen-centered radicals in vivo with reduced glutathione through glutathione peroxidase. It is believed that selenium-GSH peroxidase catalyzes toxic hydrogen peroxide in the presence of reduced glutathione. This reaction reduces glutathione to oxidized glutathione (GSSG). In turn, the GSSG is reduced back to GSH by the enzyme GSH reductase thereby maintaining abundant cellular GSH to scavenge free radicals anew. GSH reductase is provided in these preparations through thiol rich yeast extracts.
It is further contemplated that the present composition, as a preferred embodiment, includes acetyl L carnitine. This latter component further participates in protecting cells against lipid peroxidation by locally increasing the amount of antioxidizing agents of GSH and ubiquinol. L-carnitine, also known as gamma trimethylamino-beta hydroxy butyrate or Vitamin Bt, occurs naturally in the body. It is a normal endogenous intermediary metabolite which has been identified in all mammalian cells and in blood and urine. It has the function of transporting fatty acids and other acidulated compounds across inner mitochondrial membranes and of maintaining the acyl CoA/free CoA ratio between the mitochondria and the cytosol of the cells. Acetyl L carnitine is the acetyl derivative of l-carnitine and is also a naturally occurring substance in the body as it provides a transport mechanism for the acetyl groups created by the beta oxidation of fatty acids while concomitantly regenerating acetyl co-enzymes in the cytosol of the cell.
Of interest herein, acetyl L carnitine has been shown to have a scavenging effect on the free superoxide anion. This antioxidant activity coupled by acetyl L carnitine""s effect of inducing an increase in reduced glutathione and reduced ubiquinone levels provides a stabilizing effect on membranes by decreasing membrane lipid peroxidation.
The skin is a highly vascular organ, extracellularly very rich in polyunsaturated fatty acids. The skin exposed to ultraviolet rays with its exposure to atmospheric oxygen is most prone to the process of lipid peroxidation and thus skin may be readily damaged acutely and/or chronically by this radiation, both UVA and UVB. Thus, reduced glutathione and acetyl L carnitine in a topical preparation will act somewhat synergistically; the former as a reparative antioxidant which itself becomes oxidized and better able to be regenerated locally in its reduced form by the metabolic functions of acetyl L carnitine and by acetyl L carnitine""s ability to enhance mitochondrial energy production. This is accomplished by the latter""s actions on lipid metabolism and by the resulting increase in cytochrome oxidase, the final enzyme in the cellular respiratory chain.
Further, glutathione and selenium act synergistically in vivo as they are both constituents of the same enzymatic system. GSH serves as a specific donor substrate while selenium, provided from alimentary sources or locally from topically applied preparations of selenoamino acids, selenium yeast extracts or selenoamino acid chelates, provides the prosthetic group of GSH peroxidase, during its synthesis. The glutathione and selenium antioxidant functions are intrinsically related since by keeping a peroxidase in action, the GSH and selenium, contribute to the removal of the dismutation product of free oxygen radicals, namely, hydrogen peroxide. In a broad sense, GSH and selenium modulate free radical chains initiated or sustained by hydro peroxides.
Selenium is used in the present invention for its role as an antioxidant as well as its anticarcinogenic and antimutagenic properties. Selenium is an essential trace element, and a cofactor and constituent of the enzyme glutathione peroxidase. Selenium preparations as a sulfide have been used as topical antiseborrheic detergents (Selsun(copyright)) and in veterinary medicine topically for eczemas and dermatomycoses.
Selenomethionine decomposes lipid peroxides and inhibits in vivo lipid peroxidation in tissues of vitamin E deficient chicks. Other selenoproteins also show a high degree of inhibition of lipid peroxidation in hepatic tissues of various species, thus concluding that in vivo selenium exhibits antioxidant behavior.
Selenium has also been shown to affect the immune system. Selenium supplementation as 70% selenomethione in patients with psoriasis with normal pretreatment selenium blood levels showed an increase in blood levels of 40% post treatment, although skin levels of selenium dependent glutathione peroxidase were unchanged in both normal and psoriatic skin. A statistically significant increase in the number of CD4+T-cells was noted in the reticular dermis of the psoriatic lesions.
In other studies in human subjects, optical selenomethionine was investigated for its ability to reduce the degree of acute damage to the skin by sunburn as induced experimentally by ultraviolet irradiation. Eight women were treated for two weeks with a lotion vehicle and then with three concentrations of selenomethionine (0.002%, 0.02% and 0.05%). The researchers found that topical selenomethione was effective in protecting against acute UV damage to the skin, as measured by the minimal erythema dose, using a multiport solar ultraviolet simulator. Plasma levels of selenium in these volunteers remained unchanged, suggesting the protective effect of the selenomethionine was locally at the skin.
The effects demonstrated by topical selenomethinine in human volunteers (Burke et al.) on measurement of minimal erythema dose, suggests that the protection to ultraviolet irradiation by this compound is not simply a sunscreen effect. The selenomethionine is absorbed percutaneously and acts locally as a free radical scavenger, after absorption from the outer skin layers, acting most likely as the co-factor for the enzyme glutathione peroxidase. Thus, even if the person perspires or goes swimming, selenomethionine continues to afford its protective effect as a local antioxidant and not as a sun blocker, which needs to be reapplied to the skin to render its value as a protectant or absorber of UV irradiation. No selenium toxicity is possible at the doses used in these topical compositions (0.001 to 0.05% with an average dose at 0.025%) for studies have indicated selenium toxicities occur in excess of oral 4000 micrograms per day for prolonged periods. Like all sunscreen-sun blocking preparations, the compositions disclosed herein require that the active, synergistic complex, which includes selenoamino acid or selenium yeast extract and reduced glutathione be applied topically by the individual about 30 minutes prior to the expected exposure to solar radiation. Moreover, persons expected to be exposed to solar radiation need to heed the other well known sun safety measures, including coverups with clothing, hats and sunglasses.
Compositions of reduced glutathione in the present invention comprise from about 0.001%, preferably from about 0.1% to 15%, more preferably from about 1% to 5% by weight.
The lower limit of concentration for selenomethionine is selected to achieve a composition in which its amount in the topical preparation provides a therapeutic concentration of the selenoamino acid, no lower than 0.001%. The concentrations to be employed are between 0.001% and 5%, but preferably from 0.01 to 1.0% but most preferably from 0.015 to 0.05% by weight.
xe2x80x9cCell growth stimulating compounds or factorsxe2x80x9d have been described as natural or exogenous compounds which have a stimulating effect on the elaboration and growth of specific cell lines. These include anabolic growth hormones, as human growth hormone and thyroid stimulating hormone, or on specific cell lines as granulocytes, platelets or erythrocytes. Specifically, in regard to promoting epidermal growth, such as in skin tissue repair or wound healing, various factors have been identified as growth factors, including epithelial (epidermal) growth factor (EGF), fibroblast growth factor (FGF), tissue respiratory factor (TRF), transforming growth factor (TGF) and insulin-like growth factor (IGF).
In the present formulations using antioxidants and anti-inflammatory compounds, one or more cell growth stimulating compounds in suitable amounts effective for stimulating the growth of cells which encompass or surround and are injured or are responsible for healing wounds may be incorporated in the preparation of the present creams, balms, lotions, solutions or gels; patches, sprays or other cosmetic and foundation compositions. Skin cellular reparative functions of dermatologic injuries or lesions (sunburn, gamma radiation and laser burns, chemosurgery, dermatoses, etc.) are included in the list of therapies as examples.
Also useful herein is a component known as tissue respiratory factor (TRF). TRF is a live yeast cell derivative which has been used in over the counter pharmaceutical preparations since the 1940""s and more recently as an ingredient in cosmetics. It is commercially available (Brooks Industries Biodynes-TRF(trademark), South Plainfield, N.J.) and purported to be a powerful internal moisturizer which refreshes dry and infirm skin. TRF was first used as an anti-hemorrhoidal product (Preparation Hxc2x0, Whitehall Laboratories). TRF is composed of low molecular weight glycosidic/peptide fractions, with a ratio of 1:3. The residual glycopeptide linkages are through the amino acid asparagine residues. Because TRF is prepared from live yeast cells derivatives, additional trace quantities of coenzymes, vitamins, amino acids and minerals, characteristic of yeast, are available in these factors, which enhance the therapeutic capabilities of TRF in these pharmaceutic/cosmetic preparations.
TRF has a maximum absorbance of 13.0-20.0; ultraviolet spectrophotometer of a 1% TRF filtered solution reads at 256-258 NM. It is available as a water soluble material for gels, emulsions, lotions and creams. TRF has been shown to promote wound healing through its ability to increase fibroblast synthesis of collagen and elastin fibers resulting in smoothing of the skin. TRF""s moisturizing effect is accomplished by increasing uptake of moisture by nascent protein and increasing oxygen utilization in the skin. TRF has been used in the treatment of sunburned skin and has been preferred for decreasing pain and discomfort of sunburn damaged skin when compared to a topical post-sun product containing the local anesthetic benzocaine. Thus, TRF, as other growth factors, may be used in combination to these proposed antioxidant preparations as a preventive and prophylactic agent to photodamaged, burned, irradiated or inflamed skin of diverse etiologies.
A further optional expedient is the use of epidermal growth factor (EGF). Epidermal growth factor is an endogenous substance for the development and maintenance of the epidermis and dermis. EGF is a protein that catalyzes the cutaneous healing process by promoting epidermal and epithelial cells to divide and grow. It induces mitoses, so that skin constantly produces and uses EGF, particularly when skin is damaged, such as in ultraviolet radiation and after surgery, and trauma for both healing and reduction of scar and keloid formation. When applied topically, EGF generates and replaces epithelial cells. EGF also promotes synthesis of proteins, accumulation of collagen and formation of blood vessels. Following sunlight injury and during the aging process, topical application of EGF replaces the existing low levels of dermal growth factors to achieve improvement in the quality of the skin, thereby reducing sagging skin and wrinkles. The antioxidants protect and repair damaged skin from free radicals while the growth factors to be used in combinations will promote epidermal cell renewal and thus ensue in repair of affected tissues, minimizing photodamage and mutations which promote cutaneous carcinogenesis.
Epidermal growth factor is a 53 amino acid polypeptide which stimulates messenger RNA, DNA and protein synthesis. In vitro it stimulates keratinocyte division and in vivo epidermal cell regeneration.
After cutaneous injury, residual epithelial cells proliferate in an organized fashion to regenerate an intact epidermis. Superficial wounds which do not result in total skin loss but retain at least a portion of the dermal layer, heal primarily by this process of epidermal regeneration. Epidermal growth factor induces replacement of cells by inducing mitosis. Many experiments, animal and human studies, have positively shown the beneficial effect of EGF in the process of wound repair. These clinical situations include partial thickness burns, skin graft donor sites, and chronic skin ulcers. It is also of use in healing radiation skin burns, surgical scars and in the repair process of cosmetic surgeries and cutaneous chemical peels.
Thiol rich yeast extracts also provide glutathione peroxidase and the sulphur groups to promote its synthesis and enhance the glutathione pathways. Thiol yeast extracts are used in concentrations ranging from 0.5% to 8%, most typically 3-5% and usually at 3.75 to 4.25% by weight.
As noted previously, the active ingredients described above can be incorporated in any suitable pharmacologically acceptable carrier which is suitable for topical administration to the human skin. As such, the pharmacologically acceptable carrier must be of sufficient purity and have sufficiently low toxicity to render it suitable for administration to a human noting that, typically, the carrier can represent up to 99.99% and typically from at least approximately 80% of the total composition.
Typical compositions for use herein include a wide variety of physical forms. These include, but are not limited to, solutions, lotions, creams, oils, gels, sticks, sprays, ointments, balms, patches and pastes. Generally, such carrier systems can be described as being solutions, creams, emulsions, gels, solids and aerosols.
Solvents are generally employed in the preparation of suitable topical compositions. Such solvents can either be aqueous or organic based and, in either case, the solvent must be capable of having dispersed or dissolved therein the above-described active components while not being irritating to the user. Water is a typical aqueous solvent while suitable organic solvents include propylene glycol, battalion glycol, polyethylene glycol, polypropylene glycol, glycerol, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol, ethanol, isopropanol, butanediol and mixtures thereof. Solvents can be included in the overall composition in amounts ranging from 0.1% to 99% and preferably from 2.0% to 75%. It is noted that compositions of the present invention can be produced in the form of an emollient. A wide variety of suitable emollients are known and may be used herein. In this regard, reference is made to U.S. Pat. No. 5,296,500, the disclosure of which is incorporated by reference.
Alternatively, the present composition can be formulated as a lotion containing from about 0.01% to 10% of the above described active ingredients. Further, the product can be formulated from a solution carrier system as a cream. A cream of the present invention would preferably comprise from about 0.1% to 15% and preferably from 1% to 5% of the above described active ingredients. Lotions and creams can be formulated as emulsions as well as solutions.
It is contemplated that as one embodiment, the active ingredients described above be used as a lotion or cream emulsion of the oil-in-water type or as a water-in-oil type, both of which being extremely well known in the cosmetic field. Multi-phase emulsions such as the water-in-oil type is disclosed in U.S. Pat. No. 4,254,105, the disclosure of which is incorporated herein by reference.
It is further contemplated that the active ingredients of the present invention be formulated from a solution carrier system as an ointment. An ointment may comprise a simple base of animal or vegetable oils or semi-solid hydrocarbons (oleaginous). Ointments may also comprise absorption ointment bases which absorb water to form emulsions. Ointment carriers may also be water soluble. An ointment may comprise from 1% to 99% of an emollient plus to about 0.1% to 99% of a thickening agent. Reference is again made to U.S. Pat. No. 5,296,500 and the citations contained therein for a more complete disclosure of the various ointment, cream and lotion formulations for use herein.
It is important to supply locally both glutathione and the synergistic antioxidants to restore epidermal glutathione levels and enhance the reparative antioxidant chain breaking reactions. It becomes imperative to prevent UV ray damage by prophylaxis with skin care (sun protection) products and appropriate clothing, plus the prevention of free radicals and their neutralization by locally applied chain-breaking antioxidant preparations, as proposed in the present application.